Potassium (K+) channels serve diverse and critical roles in neuronal signaling and mutations in K+ channel genes have been linked to human neurological diseases such as epilepsy. Nevertheless, significant gaps still exist in our understanding of how K+ channels control neuronal excitability. For example, the Kv12 gene family is among the oldest and most highly conserved K+ channel families, yet the physiological function of these channels has not previously been examined in vivo due to a lack of genetic and pharmacologic tools. To address this knowledge gap, we have generated a mouse knockout of the voltage-gated K+ channel Kv12.2. The knockout mice have spontaneous epilepsy and a pronounced sensitivity to the chemoconvulsant pentylenetetrazol, suggesting a key role for Kv12.2 in the regulation of neuronal excitability. We find that hippocampal pyramidal neurons cultured from Kv12.2 knockout mice have significantly depolarized resting potentials, high input resistance and low spike thresholds. Spontaneous firing rates in these knockout neurons are ~10-fold higher than in WT neurons. The goal of this research project is to determine how Kv12.2 controls excitability in neurons and circuits, and to determine how loss of Kv12.2 leads to epilepsy. This will be accomplished through a combination of genetic, biochemical, pharmacological and electrophysiological approaches. The research will provide valuable new insights into the control of neuronal firing and will provide a critical assessment of the value of Kv12.2 as a therapeutic target for antiepileptic drugs. PUBLIC HEALTH RELEVANCE: We have developed a novel and unique animal model of epilepsy by knocking out the potassium channel Kv12.2 in the mouse. The research in this proposal is designed explore the role of Kv12.2 in neuronal signaling in order to understand how loss of this potassium channel leads to seizure susceptibility and epilepsy. This research will provide valuable new insights into mechanisms of seizure control and thus addresses a critical need for new clinical strategies for the control of epilepsy.